The present invention relates to benzo[f]naphthyridine derivatives of formula (I): 
salts thereof, processes for preparing such compounds, and compositions comprising them.
European patent application no. EP 431 991 discloses benzo[b]naphthyridine derivatives of formula: 
in which R1 is H, hydroxyl or alkyl, R2 is H, alkyl, fluoroalkyl, cycloalkyl, alkyloxy or alkylamino, R3 is optionally substituted phenyl or phenylalkyl, and R4 is H or a fluorine atom. These compounds are useful as antimicrobial agents.
French patent application no. FR 2 258 855 describes benzo[h]naphthyridine derivatives of formula: 
in which R is an alkyl radical, and R1, R2 and R3, which are identical or different, are chosen from H, alkyl, polyhaloalkyl, halogen, alkoxy, nitro, alkylsulphone, sulphamide, or R1 and R2 or R2 and R3 may be linked to each other to constitute a novel saturated or unsaturated carbon-containing ring comprising 5 or 6 carbon atoms, it being possible for the bonding between these radicals themselves and the base nucleus to take place via one or two heteroatoms of oxygen to form a novel heterocycle. These compounds are useful as antimicrobial agents.
U.S. Pat. No. 3,300,499 describes benzo[f]naphthyridine derivatives of formula: 
in which X is a carboxyl or alkyloxycarbonyl group, R1 is an alkyl or alkenyl group, and the 5, 7, 8, 9 and 10 positions may also carry substituents chosen from alkyl, alkyloxy, hydroxyl, halogen, alkylamino and alkylthio.
However, these compounds have not been found to be active in tests for bacteriological activity in vitro carried out by the instant inventors.
The inventors have now found that benzo[f]naphthyridine derivatives of formula (I), salts thereof, and, where appropriate, stereoisomers thereof or mixtures of stereoisomers thereof: 
wherein:
R1, R2, and R3, which are identical or different, may each be chosen from a hydrogen atom, halogen atoms, and groups of formula (II): 
xe2x80x83wherein:
R5 and R6 form, together with the nitrogen atom to which they are attached, a 5-, 6-, or 7-membered heterocycle, wherein 2 carbon atoms may optionally be linked to each other by a bridge containing 1 or 2 carbon atoms, wherein the heterocycle optionally comprises, in addition to the nitrogen atom, a heteroatom chosen from nitrogen, oxygen, and sulphur, and wherein the heterocycle may be optionally substituted with at least one group chosen from (i) an unsubstituted phenyl group, (ii) a phenyl group substituted with at least one group chosen from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, and a benzyloxy group, (iii) a benzyl group, (iv) alkyl groups, (v) a hydroxyl group, (vi) aminoalkyl groups, (vii) alkylaminoalkyl groups, (viii) dialkylaminoalkyl groups, and (ix) benzylaminoalkyl groups,
provided that at least one of groups R1, R2, and R3 is a group of formula (II), and
provided that at least one of groups R1, R2, and R3 is chosen from halogen atoms,
R4 is chosen from alkyl groups, fluoroalkyl groups, carboxyalkyl groups, (C3 to C6) cycloalkyl groups, a fluorophenyl group, a difluorophenyl group, alkyloxy groups, and alkylamino groups, and
wherein the alkyl groups may be chosen from unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups,
manifest advantageous antibacterial activity, for example, for the topical route.
In formula (I), the halogen substituents may be chosen from a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom. Moreover, when R5 and R6 form, together with the nitrogen atom to which they are attached, a 5- to 7-membered heterocycle, the heterocycle may be chosen, with no limitation being implied, from pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, perhydroazepine, and perhydrodiazepine. In addition, the above-mentioned alkyl groups can be chosen from a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and a tert-butyl group.
According to one embodiment of the present invention, the benzo[f]naphthyridine derivatives can be chosen from derivatives of formula (I), salts thereof, and, where appropriate, stereoisomers thereof or mixtures of stereoisomers thereof: 
wherein:
R1, R2, and R3, which are identical or different, may each be chosen from a hydrogen atom, halogen atoms, and groups of formula (II): 
xe2x80x83wherein:
R5 and R6 form, together with the nitrogen atom to which they are attached, a 6- or 7-membered heterocycle, wherein 2 carbon atoms may optionally be linked to each other by a bridge containing 1 or 2 carbon atoms, wherein the heterocycle optionally comprises an additional nitrogen atom, and wherein the heterocycle may be optionally substituted with at least one group chosen from (i) an unsubstituted phenyl group, (ii) a phenyl group substituted with at least one group chosen from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, and a benzyloxy group, and (iii) alkyl groups,
provided that at least one of groups R1, R2, and R3 is a group of formula (II), and
provided that at least one of groups R1, R2, and R3 is chosen from halogen atoms,
R4 is chosen from alkyl groups and fluoroalkyl groups, and
wherein the alkyl groups may be chosen from unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups.
According to the invention, compounds of formula (I) may be prepared, for example, by reacting an amine of formula (III): 
wherein:
R5 and R6 form, together with the nitrogen atom to which they are attached, a 5-, 6-, or 7-membered heterocycle, wherein 2 carbon atoms may optionally be linked to each other by a bridge containing 1 or 2 carbon atoms, wherein the heterocycle optionally comprises, in addition to the nitrogen atom, a heteroatom chosen from nitrogen, oxygen, and sulphur, and wherein the heterocycle may be optionally substituted with at least one group chosen from an (i) unsubstituted phenyl group, (ii) a phenyl group substituted with at least one group chosen from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, and a benzyloxy group, (iii) a benzyl group, (iv) alkyl groups, (v) a hydroxyl group, (vi) aminoalkyl groups, (vii) alkylaminoalkyl groups, (viii) dialkylaminoalkyl groups, and (ix) benzylaminoalkyl groups,
with a benzo[f]naphthyridine derivative of formula (IV): 
wherein:
R4 is chosen from alkyl groups, fluoroalkyl groups, carboxyalkyl groups, (C3 to C6) cycloalkyl groups, a fluorophenyl group, a difluorophenyl group, alkyloxy groups, and alkylamino groups optionally comprising a protecting group, and
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms,
wherein the halogen atoms may be chosen from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom,
separating the amine-containing compounds thus prepared, and
optionally converting the separated compound formed above to a salt.
The reaction of amines of formula (III) can be performed in the presence of an excess of a derivative of formula (III), as an acid acceptor in suitable organic solvents. It is possible to carry out the procedure with or without solvent, at a temperature ranging, for example, from 20 to 150xc2x0 C. When the procedure is carried out in the presence of a solvent, the reaction can be carried out in aprotic polar solvents, such as, for example, pyridine, dimethylformamide, dimethyl sulphoxide, and acetonitrile. It is also possible to carry out the procedure in an aqueous medium.
Such reactions may also be carried out in the presence of an acid acceptor such as, for example, a nitrogenous organic base (for example, triethylamine), an alkali metal carbonate (for example, sodium carbonate), or an alkali metal or alkaline-earth metal hydroxide.
When an amine of formula (III) is reacted with a benzo[f]naphthyridine derivative of formula (IV), a mixture of monoamine-containing compounds is obtained. These compounds may be separated by conventional separation techniques, for example by crystallization, or by preparative chromatography, such as, High-Performance Liquid Chromatography (HPLC) or medium-pressure chromatography (xe2x80x9cflash chromatographyxe2x80x9d), so as to select a desired compound of formula (I).
Benzo[f]naphthyridine derivatives of formula (IV) may be prepared, for example, from a corresponding ester of formula (VI): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms,
R4 is chosen from alkyl groups, fluoroalkyl groups, carboxyalkyl groups, (C3 to C6) cycloalkyl groups, a fluorophenyl group, a difluorophenyl group, alkyloxy groups, and alkylamino groups optionally comprising a protecting group, and
R is chosen from unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups, and
wherein the halogen atoms are chosen from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom,
by any known method for obtaining an acid from an ester without affecting the remainder of the molecule.
The preparation of an acid from an ester can generally be carried out by saponification in the presence of potassium hydroxide or of sodium hydroxide, in an aqueous or an aqueous-alcoholic medium, at a temperature ranging, for example, from 20 to 10xc2x0 C. It is also possible to carry out the procedure by acid hydrolysis at temperatures as cited above.
Compounds of formulae (IV) and (VI), which may generically represented by formula (IVa): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms,
Alk is chosen from a hydrogen atom, unbranched (C1 to C4) alkyl groups, and branched (C1 to C4) alkyl groups, and
R4 is chosen from alkyl groups, fluoroalkyl groups, carboxyalkyl groups, (C3 to C6) cycloalkyl groups, a fluorophenyl group, a difluorophenyl group, alkyloxy groups, and alkylamino groups optionally comprising a protecting group,
wherein the halogen atoms are chosen from a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom,
are novel compounds, which are useful as intermediates for the synthesis of benzo[f]naphthyridines of formula (I) according to the present invention, and therefore constitute another subject of the present invention.
According to the invention, benzo[f]naphthyridine derivatives of formula (I) may also be prepared, for example, from a corresponding ester of formula (V): 
wherein:
R is chosen from unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups,
R1, R2, and R3, which are identical or different, may each be chosen from a hydrogen atom, halogen atoms, and groups of formula (II): 
xe2x80x83wherein:
R5 and R6 form, together with the nitrogen atom to which they are attached, a 5-, 6-, or 7-membered heterocycle, wherein 2 carbon atoms may optionally be linked to each other by a bridge containing 1 or 2 carbon atoms, wherein the heterocycle optionally comprises, in addition to the nitrogen atom, a heteroatom chosen from nitrogen, oxygen, and sulphur, and wherein the heterocycle may be optionally substituted with at least one group chosen from an (i) unsubstituted phenyl group, (ii) a phenyl group substituted with at least one group chosen from halogen atoms, alkyl groups, haloalkyl groups, alkyloxy groups, and a benzyloxy group, (iii) a benzyl group, (iv) alkyl groups, (v) a hydroxyl group, (vi) aminoalkyl groups, (vii) alkylaminoalkyl groups, (viii) dialkylaminoalkyl groups, and (ix) benzylaminoalkyl groups,
provided that at least one of groups R1, R2, and R3 is a group of formula (II), and
provided that at least one of groups R1, R2, and R3 is chosen from halogen atoms, and
R4 is chosen from alkyl groups, fluoroalkyl groups, carboxyalkyl groups, (C3 to C6) cycloalkyl groups, a fluorophenyl group, a difluorophenyl group, alkyloxy groups, and alkylamino groups optionally comprising a protecting group,
by any known method for preparing an acid from an ester without affecting the remainder of the molecule, and optionally converting the acid formed above to a salt.
Preparation of acids from esters can generally be carried out by saponification in the presence of potassium hydroxide or of sodium hydroxide, in an aqueous or an aqueous-alcoholic medium, at a temperature ranging from, for example, 20 to 100xc2x0 C. It is also possible to carry out the procedure by acid hydrolysis at temperatures as cited above.
When R4 is chosen from alkylamino groups comprising a protecting group, the protecting group may be chosen from amino-protecting groups that are compatible with the molecule. In one embodiment, a protecting group that may be removed simultaneously with hydrolysis of the ester can be used. Protection of the alkylamino group may be carried out by any compatible group whose use and removal does not adversely affect the remainder of the molecule. For example, the procedure may be carried out according to the methods described by T. W. Greene, Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication (1981), or the methods described by Mc OMIE, Protective Groups in Organic Chemistry, Plenum Press (1973).
Benzo[f]naphthyridine derivatives of formula (V) may be prepared, for example, by reacting an amine of formula (III) with a corresponding ester of formula (VI) as defined above, according to the same method as that described above for the reaction of an amine of formula (III) with a benzo[f]naphthyridine derivative of formula (IV), wherein a derivative of formula (I) is prepared. It is understood that where an amine of formula (III) is reacted with a benzo[f]naphthyridine derivative of formula (IV) in an aqueous medium, it is possible to directly prepare a compound of formula (I) without intermediate isolation of a derivative of formula (V).
Benzo[f]naphthyridine esters of formula (VI) may be prepared, for example, by:
a) reacting a malonate derivative of formula (IX): 
xe2x80x83wherein:
R and Rxe2x80x2, which are identical or different, may each be chosen from unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups,
with an aminoquinoline of formula (X): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms,
to form a derivative of formula (VIII): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are defined as above with respect to formula (X), and
R is defined as above with respect for formula (IX),
b) cyclizing the compound of formula (VIII), formed in (a) above, by thermal cyclization of the Gould-Jacob type, to form a compound of formula (VII): 
xe2x80x83wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are defined as above with respect to formula (X), and
R is defined as above with respect for formula (IX),
c) reacting the compound of formula (VII), formed in (b) above, with a halogenated derivative of formula R4-Hal,
xe2x80x83wherein:
R4 is chosen from alkyl groups, fluoroalkyl groups, carboxyalkyl groups, (C3 to C6) cycloalkyl groups, a fluorophenyl group, a difluorophenyl group, alkyloxy groups, and alkylamino groups optionally comprising a protecting group, and
Hal is a halogen atom chosen from a chlorine atom, a bromine atom, and an iodine atom,
to form a benzo[f]naphthyridine ester of formula (VI): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are defined as above with respect to formula (X),
R4 is defined as above with respect to formula (VII), and
R is defined as above with respect for formula (IX).
For the above-mentioned step a), the procedure can generally be carried out without solvent at a temperature ranging, for example, from 20 to 150xc2x0 C., or in aromatic solvents, chlorinated solvents, or ethers at a temperature ranging, for example, from 20 to 110xc2x0 C. Representative solvents that may be used include xylene, toluene, chloroform, methylene chloride, and diphenyl ether.
Thermal cyclization of the Gould-Jacob type can generally be carried out at a temperature ranging, for example, from 100 to 260xc2x0 C. in diphenyl ether or in the eutectic ratio of the phenyl ether/biphenyl mixture (Angeles de la Cruz et al., Tetrahedron, 48(29), pp. 6135-6150, 1992).
The reaction according to step c) as described above can generally be carried out in a basic medium at a temperature ranging, for example, from 20 to 150xc2x0 C., in an appropriate organic solvent. As compatible base, alkali metal or alkaline-earth metal carbonates, for example, potassium carbonate, sodium carbonate, and the like, may be used. In one embodiment, such a procedure can be carried out in a solvent chosen from dimethylformamide and dimethyl sulphoxide.
Aminoquinolines of formula (X), and salts thereof when they exist, are new compounds, which are useful as intermediates in the preparation of benzo[f]naphthyridine derivatives of formula (I) according to the present invention, and therefore also constitute another subject of the present invention. Aminoquinolines of formula (X) may be prepared, for example, in various ways. For example, aminoquinolines of formula (X) may be prepared, for example, by reducing a corresponding nitroquinoline of formula (XI): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms.
Such a reduction can be carried out, for example, according to known, conventional methods which do not affect the halogenated substituents, for example, by catalytic hydrogenation in an acidic medium in the presence of Raney nickel or of palladium on carbon, in an alcohol and at a temperature ranging, for example, from 20 to 60xc2x0 C. The alcohol may be chosen from, for example, methanol and ethanol.
Further, for example, aminoquinolines of formula (X) may be prepared, for example, by carrying out the procedure by the action of tin(II) chloride in an acidic aqueous medium, at a temperature ranging, for example, from 20 to 100xc2x0 C., or by reduction with iron in an acidic aqueous and alcoholic medium at a temperature ranging, for example, from 20 to 100xc2x0 C. The acidic aqueous medium may be, for example, an aqueous hydrochloric acid solution. The alcoholic solution may be, for example, chosen from methanol and ethanol.
Nitroquinolines of formula (XI) may be prepared, for example, by reacting methazonic acid with a benzaldehyde derivative of formula (XII): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms.
Such a procedure can generally be carried out at a temperature ranging, for example, from 20 to 50xc2x0 C., in an acidic aqueous medium which may be, for example, an aqueous hydrochloric acid solution.
Benzaldehyde derivatives of formula (XII) may be prepared, for example, by reacting a corresponding halogenated derivative of aniline of formula (XIII): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms, and
Halxe2x80x2 is a halogen atom chosen from a chlorine atom, a bromine atom, and an iodine atom,
with an organolithium compound in an ether at a temperature ranging, for example, from xe2x88x9275 to 20xc2x0 C., and
adding dimethylformamide. Butyllithium may be mentioned as an organolithium compound, with no limitation being implied. In one embodiment, the procedure can be carried out, for example, in tetrahydrofuran.
The compounds of formula (XIII) are commercially available or may be prepared, for example, by analogous preparation techniques used for halogenation of anilines, for example, by the action of a halosuccinimide in an aprotic polar solvent at a temperature ranging, for example, from xe2x88x9220 to 100xc2x0 C. It is possible, for example, to carry out the procedure in dimethylformamide.
Aminoquinolines of formula (X) may also be prepared, for example, by Hoffmann degradation of an amide from a corresponding carboxamide derivative of formula (XIV): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms.
The reaction can generally be carried out by the action of an oxidizing agent compatible with the reaction of Hoffmann degradation of an amide, at a temperature ranging, for example, from xe2x88x9220 to 100xc2x0 C. As an oxidizing agent compatible with the reaction, it is possible to use, for example, sodium hypobromite, lead tetraacetate, or hypervalent derivatives of iodine such as, for example, 1,1-bis(trifluoroacetoxy)-iodobenzene and the like.
It is also possible to carry out the procedure according to any known method for preparing an amine from a carboxamide without affecting the remainder of the molecule.
Carboxamide derivatives of formula (XIV) may be prepared, for example, from a corresponding carboxyl derivative of formula (XV): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms,
according to known, art-recognized amidation methods for preparing a carboxamide from a corresponding acid without affecting the remainder of the molecule.
For example, such a procedure can be carried out by addition of thionyl chloride in a chlorinated solvent at a temperature ranging, for example, from 20 to 80xc2x0 C., and then the acid chloride thus prepared can be treated with a stream of ammonia in methylene chloride at a temperature ranging, for example, from xe2x88x9210 to 20xc2x0 C. Chloroform, dichloromethane, and the like may, for example, be mentioned as chlorinated solvents.
Derivatives of formula (XV) may be prepared, for example, from corresponding esters of formula (XVI): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms, and
Rxe2x80x3 may be chosen from unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups,
by any known method for preparing an acid from an ester without affecting the remainder of the molecule.
The preparation of the acid from the ester can generally be carried out according to the methods described above.
Ester derivatives of formula (XVI) may be prepared, for example, by catalytic hydrogenation in a basic medium, in the presence of palladium on carbon, of a halogenated derivative of formula (XVII): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms,
Rxe2x80x3 may be chosen from unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups, and
Halxe2x80x3 is a halogen atom chosen from a chlorine atom, a bromine atom, and an iodine atom.
Such a procedure can generally be carried out in an alcohol, for example, methanol or ethanol, in the presence of a base, such as, triethylamine or diisopropylamine, and palladium on carbon at a temperature ranging, for example, from 20 to 60xc2x0 C.
Derivatives of formula (XVII) may be prepared, for example, by halogenating a derivative of formula (XVIII): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms, and
Rxe2x80x3 may be chosen from unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups.
Such a procedure can generally be carried out in the presence of phosphorus oxychloride or of phosphorus oxybromide, at a temperature ranging, for example, from 20 to 120xc2x0 C.
Derivatives of formula (XVIII) may be prepared, for example, from a derivative of formula (XIX): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms, and
Rxe2x80x3 may be chosen from unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups,
according to the method described in Angeles de la Cruz et al., Tetrahedron, 48(29), pp. 6135-6150 (1992).
The procedure can also be carried out in a manner similar to the method described above for passing from a derivative of formula (VIII) to a derivative of formula (VII) (step b for the preparation of benzo[f]naphthyridine esters of formula (VI)), or by any other similar known, art-recognized method.
Derivatives of formula (XIX) may be prepared, for example, by reacting an aniline derivative of formula (XX): 
wherein:
Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23, which are identical or different, may each be chosen from a hydrogen atom and halogen atoms, provided that at least two of Rxe2x80x21, Rxe2x80x22, and Rxe2x80x23 are chosen from halogen atoms,
with a malonate derivative of formula (XXI): 
wherein:
Rxe2x80x3 and Rxe2x80x2xe2x80x3, which may be identical or different, may each be chosen from
unbranched (C1 to C4) alkyl groups and branched (C1 to C4) alkyl groups, according to methods similar to that described by Angeles de la Cruz et al., Tetrahedron, 48(29), pp. 6135-6150 (1992).
Such a procedure can be carried out, for example, under operating conditions similar to those described above for passing from a derivative of formula (X) to a derivative of formula (VIII).
Aniline derivatives of formula (XX) are commercially available or may be prepared, for example, according to conventional methods, for example, by reducing a corresponding nitro derivative without affecting the halogenated substituents. Further, for example, a derivative of formula (XX) may be prepared, for example, according to conventional methods of halogenating anilines, such as is described above.
According to the invention, where appropriate, when stereoisomeric forms of the benzo[f]naphthyridine derivatives of formula (I) exist and when it is desired to obtain these stereoisomers, the separation of the stereoisomeric forms of the amines of formula (III) can be carried out by any known method compatible with the molecule. By way of example, the separation can be carried out by acylation by means of an acid or a reactive derivative of a chiral acid, separation of the isomers by high-performance liquid chromatography, and then deacylation according to the method described by P. G. Gasseman et al., J. Am. Chem. Soc., 98(5), p. 1275 (1976). It is also possible to carry out the separation of the stereoisomers by chiral phase high-performance liquid chromatography.
The new compounds according to the present invention as well as their synthetic intermediates may be optionally purified by conventional physical methods, such as crystallization or chromatography.
Compounds of formula (I) according to the present invention, as well as intermediates of formula (IV), may be converted to metal salts or to addition salts with nitrogenous bases according to known methods. These salts may be prepared, for example, according to known, art-recognized methods which do not adversely affect the remainder of the molecule, such as, for example, by reacting a metal base (for example, alkaline or alkaline-earth metal bases), ammonia or an amine with an above-mentioned compound in an appropriate solvent such as an alcohol, an ether or water, or by an exchange reaction with a salt of an organic acid. The salt formed precipitates after optional concentration of its solution, it is separated by filtration, decantation and/or lyophilization.
The new compounds according to the invention may also be converted to addition salts with acids. The compounds of formula (I) prepared in the form of these salts may be released and converted to salts of other acids according to known, art-recognized methods.
Representative pharmaceutically acceptable salts include, for example, salts with alkali metals (for example, sodium, potassium, and lithium), salts with alkaline-earth metals (for example, magnesium and calcium), ammonium salts, salts of nitrogenous bases (for example, ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N,N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzylphenethylamine, N,Nxe2x80x2-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, and dibenzylamine), as well as addition salts with inorganic acids (for example, hydrochlorides, hydrobromides, sulphates, nitrates, and phosphates), and addition salts with organic acids (for exmaple, succinates, fumarates, maleates, methanesulphonates, p-toluenesulphonates, and isethionates).
Benzo[f]naphthyridine derivatives of formula (I) according to the present invention and their pharmaceutically acceptable salts exhibit advantageous antibacterial properties. They manifest a remarkable activity in vitro and in vivo on Gram-positive microorganisms and for example on microorganisms resistant to quinolones. Taking into account their activity, they are appropriate, for example, for use by the topical route.
In vitro, compounds of formula (I) are active at a concentration ranging, for example, from 1 to 4 xcexcg/cm3, on Staphylococcus aureus IP 8203 and at a concentration ranging, for example, from 1 to 8 xcexcg/cm3, on Staphylococcus aureus LF11C128B, which are resistant to quinolones.
In vivo, the compounds are active at a concentration ranging, for example, from 2% to 5% in a cetomacrogol and benzyl alcohol formulation, in the model of infection of guinea-pigs with Staphylococcus aureus TCC25923.
Compounds according to the present invention do not exhibit toxicity at the doses used. The level of skin irritation measured in rabbits as a formulation in cetomacrogol and benzyl alcohol, is 1 for a formulation containing 1% of at least one compound according to the invention in the excipient, compared with 0.8 for the excipient alone. Furthermore, a formulation containing 10% of at least one compound according to the invention in the above excipient did not show greater irritation in guinea-pigs.
The following examples, given with no limitation being implied, illustrate the present invention.